Receptor tyrosine kinases represent a class of proteins that transduce signals from the extracellular milieu into the cytoplasm by binding peptide growth factors. These growth factors and their cognate receptors are involved in regulating cellular growth and differentiation. Alteration of either growth factors or their receptors can result in neoplastic transformation and altered development. See M. Cross and T. Dexter, Cell 64:271 (1991). There are several mechanisms by which growth factor receptors can be rendered transforming. Retroviral transduction of proto-oncogenes can result in truncation and mutation of the normal version of the gene. This has been shown for the EGF receptor (v-erbB) (J. Downward et al., Nature 307:521 (1984)), CSF-1 receptor (v-fms) (C. Sherr, Blood 75:1 (1990)) and ros (v-ros) (H. Matsushime et al., Mol. Cell. Biol. 6:3000 (1986)). Overexpression of an otherwise normal receptor, with or without the concomitant application of ligand, can also result in neoplastic transformation as shown for the IGF-1R (M. Kaleko et al., Mol. Cell. Biol. 10:464 (1990)), EGFR (P. Di Fiore et al., Cell 51:1063 (1987); T. Velu et al., Science 238:1408 (1987)), CSF-1R (M. Roussel et al., Nature (London) 325:549 (1987)), eph (Y. Maru et al., Oncogene 5:445 (1990)) and neu (P. Di Fiore et al., Science 237:178 (1987)). Furthermore, structural rearrangement, as seen with ret, trk, and met, may also activate the transforming capacity of receptor kinases. See M. Grieco et al., Cell 60:557 (1990); D. Martin-Zanca et al., Nature (London) 319:743 (1986); M. Park et al., Cell 45:895 (1986).
In addition to the transforming activity of altered or overexpressed receptor tyrosine kinases, studies have demonstrated that the normal cellular homologues of these receptors function to regulate cell growth and differentiation. Examples include the trk receptor kinase originally isolated by genomic transfection of human colon carcinoma DNA into NIH/3T3 cells. D. Martin-Zanca et al., supra. Although trk is not generally involved in colon cancer, recent work has demonstrated that this gene encodes a subunit of the nerve growth factor receptor which plays a critical role in neural development. See D. Kaplan et al., Science 252:554 (1991); R. Klein et al., Cell 65:189 (1991). Furthermore, the met proto-oncogene, originally isolated by transfection of 3T3 cells with genomic DNA from a tumorigenic human osteogenic sarcoma cell line MNNG-HOS (C. Cooper et al., Nature (London) 311:29 (1984)), has been demonstrated to be the cell-surface receptor for hepatocyte growth factor, a potential growth factor for a broad spectrum of cell types as well as a mediator of liver regeneration. D. Bottaro et al., Science 251:802 (1991). In addition, the CSF-1 receptor mediates the pleiotrophic effects of its cognate ligand, colony-stimulating factor-1 (CSF-1). Together these two molecules stimulate the proliferation and differentiation of cells of the macrophage lineage. C. Sherr, supra.
One oncogene which has been of considerable interest is neu (also known as "her2"). Methods for the detection of neu gene expression and products are disclosed in PCT Application WO 89/10412. Methods of treating tumor cells by inhibiting the function of a growth factor receptor such as HER2 receptor are disclosed in PCT Application WO 89/06692. Methods of detecting point mutations in the neu gene are disclosed in U.S. Pat. No. 4,935,341. Genes in this family are thought to be activated by the alteration of a single nucleotide in the normal cellular DNA sequence (the protooncogene), resulting in activation of the oncogene. This point mutation was initially seen in a rat neuroblastoma induced by transplacental exposure to a carcinogen.
In an effort to determine genes involved in the progression of chronic myelogenous leukemia (CML) to acute phase leukemia, we previously reported the identification of a transforming gene in the DNAs of two patients with CML. See E. Liu et al., Proc. Natl Acad. Sci. U.S.A. 85:1952 (1988). We term this gene axl (anexelekto, anexelekto=axl, Greek for "uncontrolled"). The present invention is based upon our ongoing interest in investigating this gene.